Arthritis (from the Greek word for joint) is a chronic multifactorial disease induced when the immune system attacks and begins degrading the body's joints. Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium, and comes in many forms, including calcific periarthritis, enteropathic arthritis, chronic, gouty, and hand osteoarthritis, hip and knee osteoarthritis, thumb, Jaccoud's, juvenile osteoarthritis, oligoarthritis, polyarthritis, and peripheral, psoriatic, rheumatoid, and septic arthritis. RA is triggered by an immune response generated via the molecular recognition of the T-cell receptor on CD4-positive T cells with a complex of disease-inducing peptides bound to Human Leukocyte Antigen (HLA) class II molecules.
Rheumatoid arthritis alone is estimated to affect 1% of the world's population and is twice as prevalent in women as in men. The aging population of developed countries are presents a growing market for arthritis therapies. In the US, arthritis and other rheumatic conditions affects about 15% of the population.
Rheumatoid arthritis is associated with the expression of certain HLA class II molecules. It is known that blockade of the interaction between a given class II molecule, peptide ligand, and T cell receptor inhibits specific T cell responses both in vitro and in vivo. Tumor necrosis factor α (TNFα), an inflammation-promoting cytokine is found associated with multiple inflammatory events, including arthritis, and anti-TNFα therapeutics include Enbrel® (Etanercept), Humira® (Adalimumab), and Remicade® (Infliximab).
Other therapeutic strategies which are directed at the T cell, such as total lymphoid irradiation, thoracic duct drainage, cyclosporin A, anti-CD4 monoclonal antibody, and other monoclonal antibodies directed at T cell determinants, result in some cases in clinical improvement of rheumatoid arthritis, but these therapies are also associated with side effects. For instance, conventional general immunosuppressives increase the risk of opportunistic infections and cancer.
There is no cure for arthritis or RA at present. Current therapies are aimed at alleviating the symptoms of the disease and arresting its progress using drugs such as Enbrel®. Chemotherapeutic agents such as methotrexate, cyclophosphamide and cyclosporine have been also used for alleviating symptoms. All of the above treatments have side-effect liabilities, limited effects on relapse rates and on ability to prevent exacerbation of the disease.
Thus, there is a need for new drugs which can be used alone or in combination with other drugs to combat the progression and symptoms of arthritis, in particular, RA. It has now been found that certain novel phenazine compounds facilitate recovery in subjects suffering from autoimmune diseases. Thus, the novel phenazine compounds are useful in the treatment and prevention of arthritis, RA, and other autoimmune diseases.